Exercise training reduces resting heart rate via downregulation of the funny channel HCN4

Alicia D'souza, Annalisa Bucchi, Anne Berit Johnsen, Sunil Jit R J Logantha, Oliver Monfredi, Joseph Yanni, Sukhpal Prehar, George Hart, Elizabeth Cartwright, Ulrik Wisloff, Halina Dobrzynski, Dario Difrancesco, Gwilym M. Morris, Mark R. Boyett

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Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, I f. Block of I f abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training. © 2014 Macmillan Publishers Limited.
Original languageEnglish
Article number3775
JournalNature Communications
Publication statusPublished - 13 May 2014


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